This invention relates to chromone derivatives substituted by 3-amino-2-hydroxypropoxy side chains, medicinal preparations containing the same, and the utilization of such preparations as antihypertensive agents in animals.
Compounds related to propranolol, a potent beta-blocker, constitute a large class of compounds which have profound effects on the cardiovascular system and have found utility as antihypertensive, antidysrhythmic and antianginal drugs. However, the beta-blocking properties of these compounds are often undesirable, especially in patients with coronary insufficiencies and bronchial diseases. A compound devoid of beta-blocking effect but retaining antihypertensive effect on the blood pressure of warm-blooded animals has long been sought.
Several patents disclose various compounds which either have beta-blocking properties or do not have antihypertensive effects. U.S. Pat. No. 3,891,651 discloses compounds which are amides and, it is thought, the nitrogen of the amide which is contained in the isoquinoline fragment is likely to be responsible for any activity in that compound. U.S. Pat. No. 3,816,470 discloses various salts of secondary amines with chromone-2-carboxylic acids. U.S. Pat. No. 3,812,156 discloses a method of preparing ethyl flavone-7-oxyacetate. U.S. Pat. No. 3,352,754 discloses simple 7-hydroxy or 7-alkoxy isoflavones which are not amines and which are used for various inflammatory disorders. U.S. Pat. No. 3,219,531 discloses 5,7-dioxyacetic acid flavone compounds, but no amine functions are present. U.S. Pat. No. 3,046,275 discloses 7-dialkylaminoalkoxy derivatives but does not contain any of the hydroxyl groups of the side chain which is central for activity. Various monodialkyl aminoethyl ethers of quercetin are disclosed in U.S. Pat. No. 2,861,992, but do not contain 3-amino-2-hydroxypropoxy side chains. Also not containing that side chain are the compounds disclosed in U.S. Pat. No. 2,897,211.
P. Da Re et al, J. Med. Chem., Vol. 15, 868-869 (1972), describe the testing of chromones as in formula (1), but where R.sub.3 is methyl, for beta-adrenergic blocking activity. Da Re et al. found that all the compounds were devoid of beta-blocking activity, suggesting that chromones would not be expected to have antihypertensive properties. Additionally, ethanolamine analogues of the Da Re et al. materials are disclosed in Vol. 15 pages 198-199 of the J. Med. Chem. (1972). The analogues are beta-blockers, typical of the pronethalol type which owe their activity to the 2-isopropylaminoethanol side chain. Typical 3-amino-2-hydroxypropoxy side chain furochromone compounds are disclosed in papers presented in Drugs of the Future, Vol. III, No. 8 (1978), pages 569-571; Drugs of the Future, Vol. III, No. 11, (1978), pages 816-818; and Therapie, (1977), Vol. 32, pages 111-120. None of these references, of course, even suggest that antihypertensive activity may be possible with or without beta-blocking. None of these references discloses the process of this invention.
Wang et al., Acta Pharmaceutical Sinica, Vol. 15, pages 253-256 (1980), while disclosing compounds within Formula 1 below, fails to teach hypertensive efficacy for analogues with the amine side chain substituent in the 6 or 7 position.